Within the last decade, enterococcus has become the second most common pathogen isolated in nosocomial infections. The ability of recent enterococcal isolates (i.e., Enterococcus (E.) faecium, Enterococcus (E.) faecalis) to rapidly acquire multidrug resistance to all available antimicrobials and to disseminate resistance determinants through the exchange of genetic elements has resulted in a serious therapeutic dilemma. Antibiotic resistance of enterococcus is characterized according to its susceptibility to two glycopeptides--vancomycin (VANCO) and teicoplanin (TEICO) and is accordingly divided into three major classes of VANCO resistant enterococci (VRE) (phenotypes VanA, VanB, VanC and perhaps even a new class). Enterococcal VanA isolates (E. faecium and E. faecalis) are resistant to high levels of VANCO (MIC.gtoreq.64 .mu.g/mL) and to TEICO (MIC.gtoreq.16 .mu.g/mL) and its plasmid transferable resistance is inducible by VANCO or TEICO, while class VanB isolates demonstrate moderate levels of resistance to VANCO (.apprxeq.8-64 .mu.g/mL and retain susceptibility to TEICO (MIC&lt;2 .mu.g/mL). Resistance to VanB isolates is induced by VANCO but is not thought to be transferable. Phenotypic class VanC VANCO resistance is found in Enterococcus (E.) gallinarum and Enterococcus (E.) casseliflavus, which possess low-level resistance to VANCO (MIC.gtoreq.4 and .ltoreq.32 .mu.g/mL) but retain susceptibility to TEICO (MIC.ltoreq.1 .mu.g/mL).
VanA resistant E. faecium (VREF) is intrinsically resistant to most .beta.-lactam (cell-wall active) antibiotics by virtue of the relatively low affinity of their penicillin-binding proteins (PBPs), which are important enzymes in cell wall biosynthesis. .beta.-lactam antibiotics inhibit bacterial growth through their binding of PBPs. Enterococci contain a normally low affinity PBP (PBP5) which in some recent isolates appears to be over produced and, in some cases, genetically modified.
Emergence of strains with resistance to most .beta.-lactam, aminoglycoside and quinolone antibiotics when used as monotherapy have left only glycopeptides alone and in combination with aminoglycosides as the first line of defense against isolates resistant to .beta.-lactam agents. For example, treatment of serious enterococcal infections usually includes combinations of VANCO with a number of moderately active .beta.-lactams or aminoglycosides. However, this final therapeutic option is waning to the more recent isolation of enterococcal strains with high-level resistance to glycopeptides. Due to the isolation of enterococccal organisms that produce .beta.-lactamases in addition to the discovery of VRE isolates with high resistance to nearly all .beta.-lactam antibiotics, etc. (which usually occurs following monotherapy) an increased intensity in the search to discover new and innovative anti-enterococcal drugs is ever pressing.